The nicotinic acetylcholine receptor (nAChR) is the target of synthetic, nicotine-based insecticides, called neonicotinoids. The proposed work will examine in detail the interactions of two selected neonicotinoids, imidacloprid and clothianidin, with human muscle (a[unreadable]de) and neuronal-type (a4[unreadable]2) nAChR. There are two aims. The first aim is to establish the properties of activation and modulation by imidacloprid and clothianidin of the muscle-type nAChR. The second aim is to determine the mechanisms of neuronal-type nAChR modulation by imidacloprid and clothianidin. The results will help to better define the mechanisms of insecticide toxicity, and may be useful in learning how to provide protection from neonicotinoids, as well as provide insights into designing novel, more highly selective neonicotinoids. PUBLIC HEALTH RELEVANCE: Neonicotinoids are synthetic, nicotine-based compounds used as the active ingredients in many widely used insecticides. In mammals, exposure to neonicotinoids can result in tremors and lack of coordination. The nicotinic acetylcholine receptor is the major target of neonicotinoids in mammals. The proposed work will examine the mechanisms of action of two selected neonicotinoids, imidacloprid and clothianidin, on the nAChR.